Primary MF and secondary MF
are different at their core.1

Beyond the initial diagnosis of myelofibrosis (MF), research has shown some key differences between primary and secondary MF at a molecular level that may uncover more about what may be influencing each patient’s disease course, including chronic inflammation and other clinical challenges.

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Primary MF and secondary MF
are different at their core.1

Beyond the initial diagnosis of myelofibrosis (MF), research has shown some key differences between primary and secondary MF at a molecular level that may uncover more about what may be influencing each patient’s disease course, including chronic inflammation and other clinical challenges.

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Can low JAK2 V617F allele burden be predictive of a worse prognosis?

Based on JAK2 V617F allele burden, investigators have been able to predict how patients may respond to JAK1/2 inhibition. Patients with MF with ≥50%  JAK2 V617F allele burden (n=33) had a 5.5-fold greater probability of ≥35% spleen volume reduction (SVR) compared to patients with <50% JAK2 V617F allele burden (n=36).2,3

What else could be driving disease progression in these patients?

Seeing the differences among patients reveals their unique needs.

On the surface, certain differences are clear. Primary MF develops on its own, whereas secondary MF tends to evolve after polycythemia vera or essential thrombocythemia.4 However, taking a closer look at primary and secondary MF data can help physicians recognize the diseases as distinct. Each disease state has its own natural history and molecular profile, which allows prognostic scoring systems to help assign patient risk, predict patient response, and help guide disease management.1,5 Understanding the data around the mutations that affect the disease presentation and progression may help identify more management options for MF.

Peeling back the layers of heterogeneity reveals mutations at its core.

Most patients with MF could have more mutations beyond JAK2,CALR, and MPL, which may add to the complexity and severity of each case.1,2 Patients with primary MF typically present with 3 or more somatic mutations—whereas only one mutation may be present with secondary MF—which underscores the importance of early diagnosis and management of patients with primary MF.1 A study showed that patients with primary MF (~70% of MF cases) had a lower JAK2V617F allele burden (median JAK2V617F allele burden: 47%), while those with secondary MF (~30% of MF cases) had a higher JAK2V617F allele burden (median JAK2V617F allele burden: 92% PPV‑MF; 64% PET‑MF).2,6-8
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Primary MF

3 or more somatic mutations1

90% express 1 of 3 driver mutations
(JAK2, CALR, or MPL)9,10

+2 or more high-risk mutations1*

10% are triple-negative
(nonmutated JAK2, CALR, and MPL)9

+2 or more high-risk mutations1*
~70%~30%
MF cases2,6,7

Secondary MF

1 somatic mutation1

Majority of patients express 1 mutation in a driver gene
(JAK2, CALR, or MPL)1

 

*Patients with primary MF may also have 2 or more high-risk mutations, such as ASXL1, U2AF1, SRSF2, EZH2, and/or IDH1/2.1 High-risk mutations are defined as mutations that have been shown to correlate with worsening survival or leukemic transformation.11

ASXL1=additional sex combs-like 1; CALR=calreticulin; JAK2=janus kinase 2; EZH2=enhancer of zeste homolog 2; IDH1=isocitrate dehydrogenase 1; IDH2=isocitrate dehydrogenase 2; MPL=myeloproliferative leukemia virus; PET-MF=post–essential thrombocythemia myelofibrosis; PPV-MF=post–polycythemia vera myelofibrosis; SRSF2=serine/arginine-rich splicing factor 2; STAT=signal transducer and activator of transcription; U2AF1=U2 small nuclear RNA auxiliary factor 1.

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Primary MF

Frequency of driver mutations1:

JAK2
in
50% to60%
of patients
Lower Allele Burden
Patients with primary MF have shown a lower JAK2V617F allele burden (median 47%) than patients with secondary MF (median 92% PPV-MF; 64% PET-MF)2,8
CALR
in
25% to30%
of patients
MPL
in
3% to5%
of patients

Frequency of some high-risk mutations1:

ASXL1
in
25%
of patients
SRSF2
in
10% to15%
of patients
U2AF1
in
10% to15%
of patients
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Secondary MF

Frequency of driver mutations1:

JAK2
in
95% to98%
of patients
(PPV-MF)
in
50% to60%
of patients
(PET-MF)
Higher Allele Burden
Patients with secondary MF have shown a higher JAK2V617F allele burden (median 92% PPV-MF; 64% PET-MF) than patients with primary MF (median 47%)2,8
CALR
in
20% to25%
of patients
(PET-MF)
MPL
in
2% to3%
of patients
(PET-MF)

Key distinctions within MF are reshaping perspectives.

Listen to MPN specialist Bart Scott, MD, reflect on the prognostic importance of considering how the presence of more than one somatic mutation or displaying triple-negative disease may influence MF in patients. In this video, he discusses important differences between patients with primary MF and secondary MF—and how these differences may impact prognosis.

primary vs secondary MF video
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MPN=myeloproliferative neoplasm.

How can high-risk mutations help inform prognosis?

The identification of somatic mutations in patients with primary MF includes high-risk mutations, which are thought to impact prognosis.5

  • The presence of high-risk mutations has been correlated with worse outcomes5,11
  • Can be measured with prognostic scoring via MIPSS70+ v2.012
  • May include epigenetic mutations (eg, ASXL1) that have been shown to drive disease initiation and progression1
  • May include splicing gene mutations (eg, U2AF1, SRSF2) that have been shown to amplify cytopenias1
MIPSS70+ v2.0=mutation and karyotype-enhanced international prognostic scoring system version 2.0.

Potential drivers of disease progression may complicate management of MF.13

In primary MF, the presence of additional mutations is believed to contribute to disease progression, which is driven by the overproduction of cytokines within bone marrow. This overproduction has been shown to be triggered through the hyperactivation of NFκB.

The ongoing inflammatory cascade may result in bone marrow fibrosis, splenomegaly, constitutional symptoms (eg, fatigue, pruritus, and night sweats), and cytopenias. When left untreated, increased cytokine expression may continue to damage healthy cells, tissues, and organs.14,15

Chronic inflammation1Increased cytokineexpressionIncreased cell signaling (which may include NFκB hyperactivation) Driver mutations and high-risk mutations1• Splenomegaly• Bone marrow fibrosisMay result in:• Constitutional symptoms1• CytopeniasDriver mutations and high-risk mutations1Increased cell signaling (which may include NFκB hyperactivation) Increased cytokineexpressionChronic inflammation1• Splenomegaly• Bone marrowfibrosisMay result in:• Constitutionalsymptoms1• Cytopenias

NFκB=nuclear factor kappa-light-chain-enhancer of activated B cells.

What if mutations are only part of the heterogeneity story?

Explore how cytopeniasrelate to MF phenotypes 

Specialists are sharing insights that change the MF conversation.

In his own words, Bart Scott, MD offers in-depth, personal perspective into what ongoing research into MF means to him and those within community practices today and in the future.

Explore his story at InsideMF.com

References:
  1. 1. Vainchenker W and Kralovics R. Blood. 2017;129(6):667-679.
  2. 2. Marcellino BK, et al. Clin Lymphoma Myeloma Leuk. 2020;20(7):415-421.
  3. 3. Barosi G, et al. Leukemia. 2016;30:1772-1775.
  4. 4. Harrison CN, et al. Ann Hematol. 2020;99(6):1177-1191.
  5. 5. Bose P and Verstovsek S. Int J Hematol. 2020;111(2):192-199.
  6. 6. Scotch AH, et al. Leuk Res. 2017;63:34-40.
  7. 7. Masarova L, et al. Eur J Haematol. 2018;100(3):257-263.
  8. 8. Takahashi K, et al. Blood. 2013;122(23):3784-3786.
  9. 9. Tefferi A, et al. Am J Hematol. 2018;93(3):348-355.
  10. 10. Tefferi A. Am J Hematol. 2016;91:50-58.
  11. 11. Vannucchi AM, et al. Leukemia. 2013;27:1861-1869.
  12. 12. Tefferi A, et al. Blood Cancer J. 2018;8(8):72.
  13. 13. Fisher DAC, et al. Leukemia. 2019;33(8):1978-1995.
  14. 14. Pettit K and Odenike O. Curr Hematol Malig Rep. 2017;12(6):611-624.
  15. 15. Mughal TI, et al. Int J Gen Med. 2014;7:89-101.
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